Background: The unfolded protein response (UPR) is an evolutionarily conserved, synchronized, and orchestrated process triggered by eukaryotic cells in response to endoplasmic reticulum (ER) stress. UPR restores the ER’s capacity to handle large protein loads within it, and still fold and process these proteins accurately. Many recent studies have documented the non-canonical roles of the UPR, outside of protein quality control, in the context of lipid metabolism and the immune system in cancer. Cancer cells have been known to hijack the UPR to promote survival and evade immune surveillance. However, the underlying mechanisms remain poorly understood. Objectives: Here, we critically summarize canonical and non-canonical UPR mechanisms in the contexts of tumor immune microenvironment and lipid metabolism, dissect their crosstalk with other cell fate signaling pathways within cancer, and propose therapeutic strategies to exploit this relationship. We also discuss the fundamental challenges of solely targeting UPR and emphasize the importance of patient stratification, biomarker development, and rational combination therapies to maximize the potential for therapeutic gain. We provide a deconvoluted mechanistic understanding of the UPR process in an attempt to spark prospective clinically relevant therapeutics research.
背景：未折叠蛋白反应（UPR）是真核细胞为应对内质网（ER）应激而触发的进化保守、同步协调的生物学过程。该反应旨在恢复内质网处理大量蛋白质负荷的能力，并确保这些蛋白质能够被准确折叠与加工。近期多项研究表明，UPR在蛋白质质量控制之外，还在肿瘤的脂质代谢与免疫系统中发挥着非经典作用。已知癌细胞会劫持UPR机制以促进自身存活并逃避免疫监视，但其潜在机制尚不明确。目的：本文系统梳理了UPR在肿瘤免疫微环境与脂质代谢中的经典与非经典作用机制，解析其与肿瘤内其他细胞命运信号通路的交互关系，并提出利用该关联的治疗策略。同时，我们探讨了单一靶向UPR治疗面临的核心挑战，强调患者分层、生物标志物开发及合理联合疗法对最大化治疗获益的重要性。通过对UPR机制的解构分析，本研究旨在为未来开展具有临床转化潜力的治疗策略研究提供理论依据。
肿瘤(癌症)患者之家